Malignant melanoma is one of the fastest increasing cancers in the United States, and has become a true health crisis. Retrospective epidemiologic studies have suggested that up to 80% of melanomas result from exposure to the UV spectrum of sunlight. However, the absence of a relevant mouse model for UV-induced cutaneous melanoma has been a major impediment to understanding the mechanisms of melanoma initiation and progression, and to evaluating risk factors from sunlight exposure. A major aim of the Molecular Genetics Section has been to establish such a model. Recently, we have developed a hepatocyte growth factor/scatter factor (HGF/SF) transgenic mouse model for UV-induced malignant melanoma that uniquely comprises key features of human melanomas and which, we believe, will constitute a major new investigative tool. A single dose of erythrogenic UV radiation to neonatal transgenics, but not wild type littermates, induces at a high incidence premalignant nevus-like lesions, frequently progressing to malignant melanoma with a survival-adjusted incidence of 70%. Notably, most melanocytic lesions develop in apposition with epidermal elements and possess a junctional morphology reminiscent of human melanocytic neoplasms. In contrast, chronic suberythemal UV irradiation of adult HGF/SF transgenic mice significantly accelerates non-melanoma skin cancer, but fails to induce melanocytic disease. These data are consistent with epidemiologic evidence that sporadic childhood sunburn, and not total accumulated sun exposure, is critical for melanomagenesis. This novel mouse model provides an experimental platform that is anticipated to facilitate the dissection of melanoma-associated molecular/genetic pathways, the elaboration of suspected melanoma risk factors, the evaluation of sun protection strategies and the development of efficacious immunotherapeutics. Extensive molecular, cytogenetic and linkage analyses of both familial and sporadic melanoma has implicated the INK4a locus, encoding both p16INK4a and p19ARF, as harboring the melanoma "gatekeeper" tumor suppressor. We therefore hypothesized that ink4a would play a prominent role in our murine melanoma model. However, virtually every mouse in which the HGF/SF transgene was genetically positioned on an ink4a null background selectively succumbed to highly invasive, multicentric rhabdomyosarcoma (RMS), arising at both skeletal and nonskeletal muscle sites, at a mean onset age of just 3.3 months. The resulting pathway perturbations in the mouse were mirrored in analogous human tumors; c-MET was found to be highly expressed in a majority of human RMS, frequently accompanied by either p16INK4a methylation-associated suppression, or CDK4 overexpression. Notably, the most aggressive neoplasms often harbored amplified CDK4, identifying a new candidate marker for RMS progression in patients. Our data provide the first experimental in vivo evidence linking c-Met signaling and ink4a deficiency to RMS pathogenesis. Moreover, we propose that simultaneous, reinforced disruption of myogenic growth and differentiation pathways normally regulated by c-MET, pRB- and p53 is sufficient to provoke RMS.